Abstract Project 1: Radical pleurectomy (RP) with intraoperative, pleural photodynamic therapy (pPDT) and post-operative chemotherapy produces an unprecedented median overall survival (OS) of over 41 months in patients with locally advanced, epithelial malignant pleural mesothelioma (MPM). Unlike most surgical series, >50% of RP/pPDT patients survive more than 12 months after MPM relapse; however, a subset of patients who experience early local relapse (LR, <12 mo after RP/pPDT) exhibit a rapidly progressive and fatal clinical course. One major uncertainty in these data is the how much pPDT contributes to the remarkably good outcomes. This uncertainty provides the motivation for Aim 1 of this Project, which is to perform a randomized Phase II trial in patients with epithelial MPM that will test the hypothesis that pPDT improves overall survival when added to RP followed by chemotherapy. Another uncertainty involves understanding the potential mechanisms underlying the poor prognosis for patients with early LR. Thus, Aim 1 also serves as a point of integration between the projects and cores by providing opportunities for analysis of patient-specific factors that relate to RP/pPDT patient outcome, including factors critical to pPDT dose such as light delivery and photosensitizer uptake in spatially corresponding areas. Finally, the impact of inter- and intra-patient heterogeneity on the conduct of the trial, the analysis of the data and the outcome of the patients remains unclear. Project 1 will work with the Physics and Dosimetry Core A, the Animal and Pathology Core C and the Administrative Core D to minimize the intrinsic heterogeneity of clinical practice and sample acquisition through the application of documents and protocols to standardize procedures across the Program Project. Finally, in Aim 2, the impact of heterogeneity in pPDT dose and expression of tumor-intrinsic pPDT resistance factors on patient outcome will be evaluated. This aim will test the hypothesis that time-to-local recurrence after pPDT is a function of the intra-patient heterogeneity in delivered pPDT dose (photosensitizer uptake * light fluence). We also test whether the combination of adverse tumor features (molecular/vascular phenotypes associated with PDT resistance) and large intra-patient heterogeneity in pPDT dose identifies a subset of patients at high risk for poor outcome.